WO2020029345A1 - 一种白消安组合物及其制备方法和应用 - Google Patents

一种白消安组合物及其制备方法和应用 Download PDF

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WO2020029345A1
WO2020029345A1 PCT/CN2018/102925 CN2018102925W WO2020029345A1 WO 2020029345 A1 WO2020029345 A1 WO 2020029345A1 CN 2018102925 W CN2018102925 W CN 2018102925W WO 2020029345 A1 WO2020029345 A1 WO 2020029345A1
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busulfan
cyclodextrin
organic solvent
injection
composition
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PCT/CN2018/102925
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French (fr)
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王刚
董祥玉
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江苏领航生物科技有限公司
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Priority to US15/734,537 priority Critical patent/US20210228527A1/en
Priority to EP18929739.3A priority patent/EP3834825A4/en
Priority to JP2021531154A priority patent/JP7185358B2/ja
Publication of WO2020029345A1 publication Critical patent/WO2020029345A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and relates to a busulfan composition and a preparation method and application thereof.
  • Busulfan is a bis-methanesulfonate bifunctional alkylating agent, first discovered in 1953.
  • busulfan is a cytotoxic antitumor drug. After entering the human body, its sulfonate group alkylates with guanine in tumor cells and interferes with the formation of tumor cell genetic material. , Thereby inhibiting the growth of tumor cells.
  • Busulfan is mainly used for proliferative diseases in the blood and bone marrow, especially for chronic myelogenous leukemia, primary thrombocytosis, polycythemia vera, and primary bone marrow fibrosis.
  • the busulfan injection currently on the market is only produced by Ben Venue Laboratories.Inc, and it is marketed in China after being packaged.
  • the preparation of the injection follows the patented technical method (US5559148) applied by Andersson, Borje S. et al., Using a certain proportion of a mixed solution of N, N-dimethylacetamide, polyethylene glycol 400 and water. .
  • US5559148 patented technical method
  • the reproductive toxicity of N, N-dimethylacetamide and the corrosiveness of plastic products have laid a great hidden danger for the clinical application of busulfan products.
  • crystallization of commercially available Baixiao'an injections will occur during storage, and the crystallization cannot be dissolved by shaking.
  • Crystallization will lead to the inability to calculate the dosage of the drug. Secondly, it will block the syringe needle or the capillary of the patient, which brings great inconvenience to the clinical use and increases the risk of use. Crystallized Busulfan injection cannot be used clinically and can only be destroyed, which greatly increases the cost of medication.
  • dimethylacetamide may also affect fertility.
  • DMA dimethylacetamide
  • rats 0.45g / kg / d of DMA (calculated as mg / m2, which is equivalent to 44% of the recommended daily dose of bupropion in a commercial formulation of busulfan), which can be used for 9 days in a row.
  • Rat spermatogenesis was significantly reduced.
  • Four days after artificial insemination a single subcutaneous injection of 2.2 g / kg of dimethylacetamide (calculated as mg / m2, equivalent to 27% of the dimethylacetamide contained in this product) was given to the hamster at one time, resulting in 100% The pregnancy of the test hamster was aborted.
  • the object of the present invention is to provide a busulfan composition in view of the above-mentioned disadvantages of the prior art.
  • Another object of the present invention is to provide a method for preparing the busulfan composition.
  • Yet another object of the present invention is to provide the use of a busulfan composition.
  • busulfan composition comprising the following substances in a weight ratio: busulfan: cyclodextrin is 1-20: 100-2000; preferably 1: 30-100, and more preferably 1:75.
  • the cyclodextrin is preferably sulfobutyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin, sulfobutyl-hydroxypropyl- ⁇ -cyclodextrin Any of these is more preferably SBE- ⁇ -cyclodextrin.
  • the busulfan composition is preferably prepared by the following method: dissolving busulfan in an organic solvent to obtain a busulfan solution having a concentration of 1-20 mg / mL; dissolving SBE- ⁇ -cyclodextrin with water for injection, A 10-40% (w / v) SBE- ⁇ -cyclodextrin aqueous solution was prepared; the two solutions were mixed under a nitrogen atmosphere, and after stirring for 1 hour, the organic solvent was removed; filtered, and freeze-dried.
  • bupropion it is preferable to dissolve bupropion in an environment of not higher than 35 ° C. to obtain a bupropion acetone solution having a concentration of 1-20 mg / mL.
  • the organic solvent used to dissolve busulfan is preferably acetone, methanol, ethanol, propylene glycol, or the like, and more preferably acetone.
  • composition is further preferably composed of the following components: busulfan 60 mg, SBE- ⁇ -cyclodextrin 4.5 g, acetone 10 mL, and water for injection 20 mL.
  • composition is further prepared by the following method: taking 60 mg of busulfan raw material, dissolving in 10 mL of acetone under an environment not exceeding 35 ° C; dissolving 4.5 g of sulfobutyl- ⁇ -cyclodextrin in 20 mL In water for injection; mix the two solutions, pass in nitrogen, and stir for 1 hour under a nitrogen atmosphere, remove the organic solvent, and filter the remaining solution through a 0.22 ⁇ m microporous filter, freeze dry, and seal.
  • the method for preparing the busulfan composition according to the present invention includes the following steps:
  • Method 1 Dissolve Busulfan in an organic solvent to prepare a Busulfan solution with a concentration of 1-20 mg / mL; Dissolve SBE- ⁇ -cyclodextrin with water for injection to obtain 10-40% (w / v) SBE- ⁇ -cyclodextrin aqueous solution; under nitrogen atmosphere, mix the two solutions, stir for 1 hour, remove the organic solvent; filter, freeze dry;
  • Or method two take the busulfan raw material and sulfobutyl- ⁇ -cyclodextrin into water for injection, and then add organic solvent; pass in nitrogen, stir under nitrogen atmosphere for 4 hours, remove the organic solvent, and leave the remaining solution over 0.22
  • the ⁇ m microporous membrane is filtered, freeze-dried, and sealed; the mass-volume ratio of sulfobutyl- ⁇ -cyclodextrin and water for injection is 1g: 10-40mL, and the mass-volume ratio of busulfan and organic solvents is 1- 20mg: 1mL.
  • the organic solvent used for dissolving busulfan is preferably acetone, methanol, ethanol or propylene glycol.
  • One organic solvent is more preferably acetone; the second organic solvent is more preferably ethanol.
  • busulfan composition of the present invention in the preparation of busulfan tablets or injections.
  • composition is stable without crystallizing during the dilution process, which reduces the use cost.
  • composition does not crystallize within 12 hours after the composition is diluted, which improves the safety of use
  • Figure 1 Liquid chromatogram of a busulfan composition prepared according to Example 1 after being stored at -20 ° C for 30 days.
  • FIG. 2 Liquid chromatogram of a busulfan composition prepared according to Example 1 after being stored at 40 ° C. for 30 days.
  • busulfan raw materials Take 60 mg of busulfan raw materials and dissolve in 10 mL of acetone at a temperature not exceeding 35 ° C. 2.0 g of sulfobutyl- ⁇ -cyclodextrin was dissolved in 10 mL of water for injection. The two solutions were mixed, nitrogen was passed in, and the mixture was stirred under a nitrogen atmosphere for 2.5 hours. The organic solvent was removed. The remaining solution was filtered through a 0.22 ⁇ m microporous filter, freeze-dried, and sealed.
  • busulfan raw materials 60 mg were busulfan raw materials and 3.0 g of sulfobutyl- ⁇ -cyclodextrin were added to 10 mL of water for injection, and then 10 mL of ethanol was added. Pass in nitrogen and stir for 4 hours under a nitrogen atmosphere, remove the organic solvent, and filter the remaining solution through a 0.22 ⁇ m microporous filter, freeze dry, and seal.
  • busulfan raw materials 60 mg were added to 20 mL of water for injection, and then 10 mL of methanol was added. Pass in nitrogen and stir for 4 hours under a nitrogen atmosphere, remove the organic solvent, and filter the remaining solution through a 0.22 ⁇ m microporous filter, freeze dry, and seal.
  • the busulfan injection will crystallize during storage, and the crystals cannot be dissolved by shaking. Crystallization will lead to the inability to calculate the dosage of the drug. Secondly, it will block the syringe needle or the capillary tube of the patient, which brings great inconvenience to clinical medication and increases the risk of use. Crystallized Busulfan injection cannot be used clinically, it can only be destroyed.
  • the busulfan composition prepared in Examples 1-6 was stored for 6 months and then taken out, diluted to 50 mL and 500 mL, respectively, and observed the crystals precipitated after standing for 4, 12, and 24 hours. From the results in Table 1, it can be seen that 4 hours No precipitation of crystals was detected in the interior, and it was seen that the composition had excellent dilution stability and good.
  • This patent removes the potentially dangerous dimethylacetamide in the original research.
  • the original research has crystallized during storage. Once crystallized, the dosage cannot be accurately calculated.
  • This patented product does not have re-dissolved crystallization, which improves reliability.
  • the impurity content standard is set to the total amount of impurities not to exceed 3.8%, and the composition meets the qualification requirements.
  • the busulfan composition was prepared according to Example 1, and left at -20 ° C and 40 ° C for 30 days. The related impurities were detected, and the growth of the two main impurities was compared.
  • the retention times of about 14.6 minutes and about 15.7 minutes were respectively two known impurity peaks.
  • the chromatographic peak with a retention time of about 26.1 minutes is the main peak of busulfan.
  • the impurity content standard is formulated such that the total amount of impurities must not exceed 3.8%, and the composition meets the qualification requirements.
  • the peak area is shown in Table 2.

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Abstract

本发明公开了一种白消安组合物及其制备方法和应用。一种白消安组合物，该组合物含有下列重量比的物质：白消安：环糊精为1～20：100～2000。所述的白消安组合物优选通过以下方法制备得到：将有机溶剂溶解白消安，制得浓度为1-20mg/mL的白消安溶液；用注射用水溶解SBE-β-环糊精，制得10-40％(w/v)的SBE-β-环糊精水溶液；在氮气氛围下，将两个溶液混合，搅拌1小时后，移除有机溶剂；过滤，冷冻干燥。本发明可用于片剂和注射剂。经研究证明本发明可显著性提高白消安的稳定性。本发明的注射刺激性更低，可用于临床注射，在保证产品稳定性的同时，提高了用药安全性。

Description

一种白消安组合物及其制备方法和应用 技术领域
本发明属于药物制剂领域，涉及一种白消安组合物及其制备方法和应用。
背景技术
白消安是一种双甲基磺酸酯类的双功能团烷基化剂，最早发现于1953年。从作用机理上讲，白消安属于细胞毒类的抗肿瘤药物，进入人的机体后，它的磺酸酯基团与肿瘤细胞内的鸟嘌呤发生烷化作用，干扰肿瘤细胞遗传物质的形成，从而抑制肿瘤细胞的生长。白消安主要适用于血液及骨髓方面的增殖性疾病，特别对于慢性粒细胞白血病、原发性血小板增多症、真性红细胞增多症、原发性骨髓纤维化症等疾病具有较好的疗效。但由于白消安的溶解性差，尤以水溶性最差，口服后难以吸收，且口服给药所需剂量高，同时药物吸收个体差异大，导致用量难以准确控制，因此，上市销售的白消安产品仍以注射剂为主。
目前上市销售的白消安注射剂仅由Ben Venue laboratories.Inc生产，经分装后在我国上市销售。该注射剂的制备沿用Andersson,Borje S.等人申请的专利技术方法(US5559148)，使用一定比例的N,N-二甲基乙酰胺和聚乙二醇400和水的混合配比溶液制备而成。但是，N,N-二甲基乙酰胺的生殖毒性和塑料制品腐蚀性给白消安产品的临床应用埋下了极大的隐患。同时，市售白消安注射剂在储存过程中会出现析晶现象，并且析晶无法通过震荡溶解，上市产品说明书中指出使用前应观察是否有晶体析出。析晶首先会导致药物使用剂量无法计算，其次会堵塞注射器针头或患者毛细血管，给临床用药带来了极大的不便，增加了使用风险。临床不能使用析晶的白消安注射剂，只能予以销毁，大大提高了用药成本。
已经有报道用ABS(由亚烯丙基腈，丁二烯和苯乙烯组成的聚合物)制成的硬塑料器具接触到二甲基乙酰胺(白消安市售制剂的一种辅料)使其发生分解。为防止白消安市售制剂从聚氯乙烯(PVC)容器中抽取抽提出塑化剂DEHP(二[2-乙基乙基]邻苯二甲酸盐)，应使用不含DEHP的大容量灭菌容器如玻璃或聚烯烃容器中配制白消安市售制剂的稀释溶液。给患者输注白消安市售制剂药液时，亦应使用不含DEHP的器具。
此外，二甲基乙酰胺也可能影响生育。给大鼠0.45g/kg/d的DMA(按mg/m2算，相当于白消安市售制剂每日推荐剂量中所含二甲基乙酰胺的44％)，连用9天，可使大鼠的精子生成显著减少。在人工授精后四天，给仓鼠一次性皮下注射二甲基乙酰胺2.2g/kg(按mg/m2算， 相当于本品中所含二甲基乙酰胺的27％)，结果导致100％试验仓鼠的妊娠中止。
迄今为止，尚未发现有既符合现行白消安药品标准，又具有用药安全性和长期储存稳定性的白消安注射剂的研究和报道。因此，无论从疗效的角度考虑还是从用药安全的角度或者从生产的角度考虑，制备出一种稳定的、便于长期贮存的白消安注射液是目前亟待解决的难题。
发明内容
本发明的目的是针对现有技术的上述不足，提供一种白消安组合物。
本发明的另一目的是提供白消安组合物的制备方法。
本发明的又一目的是提供白消安组合物的应用。
本发明的目的可通过以下技术方案实现：
一种白消安组合物，该组合物含有下列重量比的物质：白消安：环糊精为1～20：100～2000；优选1:30-100，进一步优选1:75。
所述的环糊精优选磺丁基-β-环糊精、羟丙基-β-环糊精、甲基-β-环糊精、磺丁基-羟丙基-β-环糊精中的任意一种，进一步优选为SBE-β-环糊精。
所述的白消安组合物优选通过以下方法制备得到：将有机溶剂溶解白消安，制得浓度为1-20mg/mL的白消安溶液；用注射用水溶解SBE-β-环糊精，制得10-40％(w/v)的SBE-β-环糊精水溶液；在氮气氛围下，将两个溶液混合，搅拌1小时后，移除有机溶剂；过滤，冷冻干燥。
其中，优选在不超过35℃的环境下，将丙酮溶解白消安，制得浓度为1-20mg/mL的白消安丙酮溶液。
用于溶解白消安的有机溶剂优选丙酮，甲醇，乙醇，丙二醇等，进一步优选为丙酮。
所述的组合物进一步优选由以下组分组成：白消安60mg，SBE-β-环糊精4.5g，丙酮10mL，注射用水20mL。
所述的组合物更进一步通过以下方法制备得到：取白消安原料60mg，在不超过35℃的环境下，溶解于10mL丙酮中；将4.5g磺丁基-β-环糊精溶解于20mL注射用水中；混合两种溶液，通入氮气，在氮气氛围下搅拌1小时，移除有机溶剂，剩余溶液经0.22μm微孔滤膜过滤后，冷冻干燥，封装。
本发明所述的白消安组合物的制备方法，包含以下步骤：
方法一：将有机溶剂溶解白消安，制得浓度为1-20mg/mL的白消安溶液；用注射用水溶解 SBE-β-环糊精，制得10-40％(w/v)的SBE-β-环糊精水溶液；在氮气氛围下，将两个溶液混合，搅拌1小时后，移除有机溶剂；过滤，冷冻干燥；
或者方法二：取白消安原料和磺丁基-β-环糊精加入注射用水中，再加入有机溶剂；通入氮气，在氮气氛围下搅拌4小时，移除有机溶剂，剩余溶液经0.22μm微孔滤膜过滤后，冷冻干燥，封装；其中磺丁基-β-环糊精和注射用水的质量体积比为1g:10-40mL，白消安和有机溶剂的质量体积比为1-20mg：1mL。
其中用于溶解白消安的有机溶剂优选丙酮，甲醇，乙醇或丙二醇，方法一种有机溶剂进一步优选丙酮；方法二中有机溶剂进一步优选乙醇。
本发明所述的白消安组合物在制备白消安片剂或注射剂中的应用。
有益效果：
本专利的白消安组合物具有以下优势：
1.不含有二甲基乙酰胺，降低了二甲基乙酰胺导致的致幻和不孕的风险。由于不含二甲基乙酰氨,本发明中不存在能降解塑料容器的成分，因此不会担心灌装容器的DEHP风险，也不用担心抽取和配置过程中器具的DEHP风险。
2.组合物稀释过程中稳定不析晶，降低了使用成本。
3.组合物稀释后12小时内稳定不析晶，提高了使用的安全性
4.组合物的稳定性获得了提高，降低了贮存成本，保障了药物有效性和安全性。
附图说明
图1依实施例1制备的白消安组合物于-20℃下存放30天后进样液相色谱图
图2依实施例1制备的白消安组合物于40℃下存放30天后进样液相色谱图
具体实施方式
实施例1：本发明白消安组合物的制备
取白消安原料60mg，在不超过35℃条件下溶解于10mL丙酮中。将4.5g磺丁基-β-环糊精溶解于20mL注射用水中。混合两种溶液，通入氮气，在氮气氛围下搅拌1小时，移除有机溶剂，剩余溶液经0.22μm微孔滤膜过滤后，冷冻干燥，封装。
实施例2：本发明白消安组合物的制备
取白消安原料60mg，在不超过35℃条件下溶解于10mL丙酮中。将6.0g磺丁基-β-环糊精溶解于20mL注射用水中。混合两种溶液，通入氮气，在氮气氛围下搅拌1小时，移除有机溶剂，剩余溶液经0.22μm微孔滤膜过滤后，冷冻干燥，封装。
实施例3：本发明白消安组合物的制备
取白消安原料60mg，在不超过35℃条件下溶解于10mL丙酮中。将2.0g磺丁基-β-环糊精溶解于10mL注射用水中。混合两种溶液，通入氮气，在氮气氛围下搅拌2.5小时，移除有机溶剂，剩余溶液经0.22μm微孔滤膜过滤后，冷冻干燥，封装。
实施例4：本发明白消安组合物的制备
取白消安原料60mg，和3.0g磺丁基-β-环糊精加入10mL注射用水中，再加入10mL乙醇。通入氮气，在氮气氛围下搅拌4小时，移除有机溶剂，剩余溶液经0.22μm微孔滤膜过滤后，冷冻干燥，封装。
实施例5：本发明白消安组合物的制备
取白消安原料60mg，和4.5g磺丁基-β-环糊精加入20mL注射用水中，再加入10mL甲醇。通入氮气，在氮气氛围下搅拌4小时，移除有机溶剂，剩余溶液经0.22μm微孔滤膜过滤后，冷冻干燥，封装。
实施例6：本发明白消安组合物的制备
取白消安原料60mg，和6.0g磺丁基-β-环糊精加入20mL注射用水中，再加入10mL甲醇。通入氮气，在氮气氛围下搅拌4小时，移除有机溶剂，剩余溶液经0.22μm微孔滤膜过滤后，冷冻干燥，封装。
本发明白消安注射液稀释稳定性实验
市售白消安注射剂说明书中指出，白消安注射剂在储存过程中会出现析晶现象，并且析晶无法通过震荡溶解。析晶首先会导致药物使用剂量无法计算，其次会堵塞注射器针头或患者毛细血 管，给临床用药带来了极大的不便，增加了使用风险。临床不能使用析晶的白消安注射剂，只能予以销毁。将实施例1-6制备的白消安组合物贮存6个月后取出，分别稀释至50mL和500mL，观察静置4、12、24小时内析出晶体的情况，由表1结果可见，4小时内都未关测到晶体析出，可见组合物具有极佳的稀释稳定性良好。
表1：白消安组合物稀释析晶实验观测结果
实施例 稀释终体积 静置4h 静置12h 静置24h
1 50 澄清透明无析出 澄清透明无析出 澄清透明无析出
1 500 澄清透明无析出 澄清透明无析出 澄清透明无析出
2 50 澄清透明无析出 澄清透明无析出 澄清透明无析出
2 500 澄清透明无析出 澄清透明无析出 澄清透明无析出
3 50 澄清透明无析出 澄清透明无析出 澄清透明无析出
3 500 澄清透明无析出 澄清透明无析出 澄清透明无析出
4 50 澄清透明无析出 少量析晶 少量析晶
4 500 澄清透明无析出 少量析晶 少量析晶
5 50 澄清透明无析出 少量析晶 少量析晶
5 500 澄清透明无析出 少量析晶 少量析晶
6 50 澄清透明无析出 澄清透明无析出 少量析晶
6 500 澄清透明无析出 澄清透明无析出 少量析晶
白消安组合物稳定性实验
本专利去除了原研中有潜在风险的二甲基乙酰胺。原研存在贮存过程中析晶的情况，一旦析晶，剂量则无法准确计算，本专利产品不存在复溶析晶，提高了可靠性。
组合物稳定性研究时，对含量和两个主要杂质进行考察，参考药典，杂质含量标准拟定为杂质总量不得超过3.8％，本组合物达到合格要求。
依实施例1制备白消安组合物，在-20℃和40℃条件下放置30天，检测其中相关杂质，对比两个主要杂质的增长量。
样品检测条件：
采用高效液相色谱法进行测定
色谱条件：C 18色谱柱(250mm×4.6mm，5um)，流动相：乙腈：水：四氢呋喃＝55：25：20(V： V)，流速：1.0mL/min。检测波长：278nm。进样量：20uL。柱温：30℃。
数据分析：
测定液相图谱中，保留时间为14.6分钟左右和15.7分钟左右的分别为两个已知杂质峰。保留时间为26.1分钟左右的色谱峰为白消安主峰。参考药典，杂质含量标准拟定为杂质总量不得超过3.8％，本组合物达到合格要求。峰面积见表2，对比可见，组合物形式的白消安经-20℃和40℃的条件存放30天，含量仅下降1.2％，可见白消安组合物获得了良好的稳定性。
表2 白消安组合物在-20℃和40℃的条件存放30天后杂质与白消安的液相峰面积变化
  -20℃ 40℃
峰1 0.113％ 0.937％
峰2 1.285％ 1.656％
峰3 98.602％ 97.407％

Claims (10)

  1. 一种白消安组合物，其特征在于该组合物含有下列重量比的物质：
    白消安：环糊精为1～20：100～2000；优选1:30-100，进一步优选1:75。
  2. 根据权利要求1所述的白消安组合物，其特征在于所述的环糊精选自磺丁基-β-环糊精、羟丙基-β-环糊精、甲基-β-环糊精、磺丁基-羟丙基-β-环糊精中的任意一种，优选为SBE-β-环糊精。
  3. 根据权利要求1所述的白消安组合物，其特征在于所述的白消安组合物通过以下步骤制备得到：
    将有机溶剂溶解白消安，制得浓度为1-20mg/mL的白消安溶液；用注射用水溶解SBE-β-环糊精，制得10-40％(w/v)的SBE-β-环糊精水溶液；在氮气氛围下，将两个溶液混合，搅拌1小时后，移除有机溶剂；过滤，冷冻干燥。
  4. 根据权利要求3所述的白消安组合物，其特征在于在不超过35℃的环境下，将丙酮溶解白消安，制得浓度为1-20mg/mL的白消安丙酮溶液。
  5. 根据权利要求4所述的白消安组合物，其特征在于用于溶解白消安的有机溶剂选自丙酮，甲醇，乙醇或丙二醇，优选丙酮。
  6. 根据权利要求1-5中任一项所述的白消安组合物，其特征在于所述的组合物由以下组分组成：白消安60mg，SBE-β-环糊精4.5g，丙酮10mL，注射用水20mL。
  7. 根据权利要求6所述的白消安组合物，其特征在于所述的组合物通过以下方法制备得到：取白消安原料60mg，在不超过35℃的环境下，溶解于10mL丙酮中；将4.5g磺丁基-β-环糊精溶解于20mL注射用水中；混合两种溶液，通入氮气，在氮气氛围下搅拌1小时，移除有机溶剂，剩余溶液经0.22μm微孔滤膜过滤后，冷冻干燥，封装。
  8. 权利要求1-5中任一项所述的白消安组合物的制备方法，其特征在于包含以下步骤：
    方法一：将有机溶剂溶解白消安，制得浓度为1-20mg/mL的白消安溶液；用注射用水溶解SBE-β-环糊精，制得10-40％(w/v)的SBE-β-环糊精水溶液；在氮气氛围下，将两个溶液混合，搅拌1小时后，移除有机溶剂；过滤，冷冻干燥；
    或者方法二：取白消安原料和磺丁基-β-环糊精加入注射用水中，再加入有机溶剂；通入氮气，在氮气氛围下搅拌4小时，移除有机溶剂，剩余溶液经0.22μm微孔滤膜过滤后，冷冻干燥，封装；其中磺丁基-β-环糊精和注射用水的质 量体积比为1g:10-40mL，白消安和有机溶剂的质量体积比为1-20mg：1mL。
  9. 根据权利要求8所述的制备方法，其特征在于用于溶解白消安的有机溶剂选自丙酮，甲醇，乙醇或丙二醇，方法一种有机溶剂优选丙酮；方法二中有机溶剂优选乙醇。
  10. 权利要求1-5中任一项所述的白消安组合物在制备白消安片剂或注射剂中的应用。
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